title: MicroRNA-150 expression induces myeloid differentiation of human acute leukemia cells and normal hematopoietic progenitors.
abstract: In acute myeloid leukemia (AML) and blast crisis (BC) chronic myeloid leukemia (CML) normal differentiation is impaired. Differentiation of immature stem/progenitor cells is critical for normal blood cell function. MicroRNAs (miRNAs or miRs) are small non-coding RNAs that interfere with gene expression by degrading messenger RNAs (mRNAs) or blocking protein translation. Aberrant miRNA expression is a feature of leukemia and miRNAs also play a significant role in normal hematopoiesis and differentiation. We have identified miRNAs differentially expressed in AML and BC CML and identified a new role for miR-150 in myeloid differentiation. Expression of miR-150 is low or absent in BC CML and AML patient samples and cell lines. We have found that expression of miR-150 in AML cell lines, CD34+ progenitor cells from healthy individuals, and primary BC CML and AML patient samples at levels similar to miR-150 expression in normal bone marrow promotes myeloid differentiation of these cells. MYB is a direct target of miR-150, and we have identified that the observed phenotype is partially mediated by MYB. In AML cell lines, differentiation of miR-150 expressing cells occurs independently of retinoic acid receptor α (RARA) signaling. High-throughput gene expression profiling (GEP) studies of the AML cell lines HL60, PL21, and THP-1 suggest that activation of CEPBA, CEBPE, and cytokines associated with myeloid differentiation in miR-150 expressing cells as compared to control cells contributes to myeloid differentiation. These data suggest that miR-150 promotes myeloid differentiation, a previously uncharacterized role for this miRNA, and that absent or low miR-150 expression contributes to blocked myeloid differentiation in acute leukemia cells.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, United States of America ; Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, United States of America.
authors.forename: Valerie A
authors.initials: VA
authors.lastname: Morris
authors.forename: Ailin
authors.initials: A
authors.lastname: Zhang
authors.forename: Taimei
authors.initials: T
authors.lastname: Yang
authors.forename: Derek L
authors.initials: DL
authors.lastname: Stirewalt
authors.forename: Ranjani
authors.initials: R
authors.lastname: Ramamurthy
authors.forename: Soheil
authors.initials: S
authors.lastname: Meshinchi
authors.forename: Vivian G
authors.initials: VG
authors.lastname: Oehler
mesh_terms: D018952:Antigens, CD34 / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics*; D045744:Cell Line, Tumor; D020869:Gene Expression Profiling / Q000379:methods; D018922:HL-60 Cells; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D020014:K562 Cells; D015470:Leukemia, Myeloid, Acute / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D022423:Myeloid Cells / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000235:genetics; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000235:genetics
chemical_list: D018952:Antigens, CD34; D035683:MicroRNAs; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; C533097:MIR150, human; C000607071:RARA protein, human